The novelty of this project lies in the combination of several cutting-edge approaches for in vivo selection and validation of functionally relevant metabolic targets in different tumor compartments, in casu cancer cells, TAMs, and T cells. The selection and validation steps are supported by unique and innovative (i) tailored metabolic gRNA libraries, (ii) clinically relevant metastatic tumor models as well as surrogate neoantigens, and (iii) transgenic mouse models. With this research, we will shed light on how metabolism and the metabolic cross-talk among cells contribute to the immunosuppressive TME, and it will build novel concepts into T cell metabolism to support T cell fitness in the adverse growth conditions of the TME. With our approach we move far beyond the current concept of targeting cancer metabolism to kill cancer cells directly. Here, we rather aim to hinder a metabolic cross-talk within the TME in order to trigger the action of the immune system.
In the short run, studying the link between metabolism and anti-tumor immunity will disclose a list of pathways and genes that are key regulators of the immunosuppressive properties of cancer cells (CDA, SLC4A4) and TAMs (GS, GLUD1, HPGDS), or that are causative for inefficient T cell fitness within the harsh TME, with particular attention to specific niches such as hypoxic regions, peri-vascular regions, different primary tumor versus metastatic sites (ad hoc designed screenings in CD8+ T cells). We will provide proof-of-concept of pharmacological targeting and initiate drug discovery campaigns within our spinoffs, with VIB Discovery Sciences and the Centre for Drug Design and Discovery, or with external industrial collaborators. Furthermore, studying how metabolism affects T cell fitness directly, will allow us to select for targets that can be safely modified ex vivo in T cells prior ACT. The ground-breaking nature is underscored by the recent green light to use the CRISPR/Cas9 platform to boost the therapeutic efficacy of patient’s T cells. Overall, our approach will not only open a brand-new way of tumor treatment but also offer the possibility to refine current tumor treatment options, as we are implementing immune checkpoint inhibitors and ACT in our experimental settings. Finally, all our effort and analysis of existing and newly generated mouse and, especially, patient samples (blood/plasma, tumor, metastasis, primary cells) will unseal the expression of the target, metabolic profiles, in situ or circulating metabolites, and new cellular neighbourhood descriptions as possible biomarkers to select the best subset of patients responding to current immunotherapies, or to one of our novel immunotherapeutic targets (i.e. companion diagnostic and predictive biomarkers), and to follow-up disease outcome (i.e. prognostic biomarkers).
